Approximately 65 million people worldwide have epilepsy. Over one-third of these individuals do not respond to current medical therapy; consequently, novel therapeutic agents are needed. Although certain brain injuries such as traumatic brain injury, stroke and prolonged status epileptics (SE) are known to predispose to epilepsy, there are currently no effective interventions to reduce the risk of epilepsy after such injuries. We and others have established that activation of the Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway occurs in the hippocampus following brain injuries that lead to epilepsy. Using a rat model of temporal lobe epilepsy (TLE), we have preliminary evidence that this activation may be a critical mediator of acquired epileptogenesis. We have observed that peripheral administration of WP1066- a JAK/STAT pathway inhibitor -at the time of SE reduces both STAT activation & spontaneous seizure frequency for 4 weeks. While it was a useful molecule for displaying proof-of-concept, WP1066 is limited by highly unfavorable chemical & pharmacokinetic (PK) properties. Our initial structure- activity relationship studies have identified one novel analog of WP1066 that has increased stability, and we have preliminary evidence that this analog, as well as two known small molecular weight JAK/STAT inhibitors that are in clinical trial or FDA approved, result in higher brain concentrations and inhibit STAT3 activation after SE more effectively than WP1066. We propose to examine these novel JAK/STAT inhibitors to determine 1) their potency to inhibit JAK/STAT pathway activation and cellular toxicity in primary hippocampal neurons, 2) brain concentrations as a function of dose and time, ability to block acute seizure- induced JAK/STAT pathway activation in brain and specificity/off-target effects on other kinases, and 3) the effects of these novel JAK/STAT inhibitors on epilepsy development and cognitive co-morbidities in a rat TLE model. The expected outcome is identification of lead JAK/STAT inhibitors that can be advanced towards clinical testing for epilepsy disease modification.